The present invention relates to hydrogel compositions and methods of preparation thereof.
Injectable polymeric hydrogels have been explored as an artificial extracellular matrix (ECM) for drug delivery and tissue remodeling/healing. These materials are attractive because of their colloidal properties in water.
Three general strategies exist for preparing injectable hydrogels. The first is based on physical interactions between polymer chains; the second strategy relies on an in situ synthesis, usually based on Michael addition chemistry; and the third strategy is based on thermoresponsive polymers. The thermoresponsive hydrogel materials are used in a variety of biotechnology applications. Thermoresponsive polymers spontaneously and reversibly undergo temperature induced viscosity change (e.g., gelation) in water. Designing thermoresponsive polymers, however, represents a significant and ongoing challenge.
Poly(N-isopropylacrylamide), PNIPAM, is a typical example of a thermoresponsive polymer, which shows a temperature-induced collapse from an extended coil to a globular structure in water upon heating above 32° C., referred to as the lower critical solution temperature for PNIPAM. Polymers that display this type of physicochemical response to thermal stimuli have been widely explored as potential injectable drug-delivery systems. However, PNIPAM is not readily biodegradable and has recently been shown to exhibit cytotoxicity.
Lutz, J. F; Hoth, A. Macromolecules 2006, 39, 893-896; and Lutz, J. F.; Akdemir O.; Hoth, A. J. Am. Chem. Soc. 2006, 40, 13046-13047 reported another class of thermoresponsive polymers derived from copolymers of 2-(2-methoxyethoxy)ethyl methacrylate (MEO2MA) and oligo(ethyleneglycol) methacrylates (OEGMA). Copolymers of MEO2MA and OEGMA exhibit lower critical solution temperatures that can be tuned between 26° C. to 90° C. simply by increasing the amount of OEGMA from 0 to 100 mole %. Significantly, the thermosensitivity of these acrylate copolymers was insensitive to concentration or ionic strength. While detailed cytotoxicity studies have not been carried out, the well known biocompatibility of polyethylene glycol (PEG) oligomers and PEG polymers suggests that copolymers of MEO2MA and OEGMA are likely to be more biocompatible than PNIPAM, although not readily biodegradable.
Another class of thermoresponsive polymers are derived using CLICK chemistry to tag hydrophobic and hydrophilic functional groups onto cyclic esters. Polymerization generates random graft copolymers having a unique balance of hydrophobic and hydrophilic functional groups. The polymers exhibit lower critical solution temperature (LCST) behavior in water at elevated temperatures.
Recent advances in synthetic polymer chemistry have enabled the development of new and powerful strategies for the controlled synthesis of complex polymer architectures, block copolymers and functional materials. Organic catalysts for the ring-opening polymerization (ROP) of heterocyclic monomers, and a number of catalyst classes have been successfully used in ROP syntheses, including DMAP, phosphines, N-heterocyclic carbenes, bifunctional thiourea-amines, and superbasic amines. The polymers derived by ROP methods include aliphatic polyesters and polycarbonates which are useful for a number of purposes including bulk packaging, resorbable medical implants, and drug delivery.
An ongoing need exists to extend synthetic advancements toward the design and preparation of new thermoresponsive polymers for injectable delivery systems.